Renal - Pharmacology

Question 1

Diuretics: site of action (546)

Answer 1

Question 2

Mannitol

• Mechanism
• Clinical use
• Toxicity

Answer 2

• Mechanism
  
  • Osmotic diuretic, increased tubular fluid osmolarity, producing increased urine flow, decreased intracranial / intraocular pressure.
• Clinical use
  
  • Drug overdose
  • Increased intracranial/intraocular pressure.
• Toxicity
  
  • Pulmonary edema, dehydration.
  • Contraindicated in anuria, CHF.

Question 3

Acetazolamide

• Mechanism
• Clinical use
• Toxicity

Answer 3

• Mechanism
  
  • Carbonic anhydrase inhibitor.
  • Causes self-limited NaHCO3 diuresis and decreased total-body HCO3- stores.
• Clinical use
  
  • Glaucoma, urinary alkalinization, metabolic alkalosis, altitude sickness, pseudotumor cerebri.
• Toxicity
  
  • Hyperchloremic metabolic acidosis, paresthesias, NH3 toxicity, sulfa allergy.
  • “ACID”azolamide causes ACIDosis.

Question 4

Furosemide

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 4

• Type of drug
  
  • Loop diuretic
• Mechanism
  
  • Sulfonamide loop diuretic.
  • Inhibits cotransport system (Na+/K+/2 Cl-) of thick ascending limb of loop of Henle.
  • Abolishes hypertonicity of medulla, preventing concentration of urine.
  • Stimulates PGE release (vasodilatory effect on afferent arteriole)
  • Inhibited by NSAIDs.
  • Increased Ca2+ excretion.
    
    • Loops Lose calcium.
• Clinical use
  
  • Edematous states (CHF, cirrhosis, nephrotic syndrome, pulmonary edema), hypertension, hypercalcemia.
• Toxicity
  
  • Ototoxicity, Hypokalemia, Dehydration, Allergy (sulfa), Nephritis (interstitial), Gout.
  • OH DANG!

Question 5

Ethacrynic acid

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 5

• Type of drug
  
  • Loop diuretic
• Mechanism
  
  • Phenoxyacetic acid derivative (not a sulfonamide).
  • Essentially same action as furosemide.
    
    • Sulfonamide loop diuretic.
    • Inhibits cotransport system (Na+/K+/2 Cl-) of thick ascending limb
      of loop of Henle.
    • Abolishes hypertonicity of medulla, preventing concentration of urine.
    • Stimulates PGE release (vasodilatory effect on afferent arteriole);
    • Inhibited by NSAIDs.
    • Increased Ca2+ excretion.
      
      • Loops Lose calcium.
• Clinical use
  
  • Diuresis in patients allergic to sulfa drugs.
• Toxicity
  
  • Similar to furosemide
    
    • Ototoxicity, Hypokalemia, Dehydration, Allergy (sulfa), Nephritis (interstitial), Gout.
    • OH DANG!
  • Can cause hyperuricemia
    
    • Never use to treat gout.

Question 6

Hydrochlorothiazide

• Mechanism
• Clinical use
• Toxicity

Answer 6

• Mechanism
  
  • Thiazide diuretic.
  • Inhibits NaCl reabsorption in early distal tubule, decreasing diluting capacity of the nephron. 
  • Decreased Ca2+ excretion.
• Clinical use
  
  • Hypertension, CHF, idiopathic hypercalciuria, nephrogenic diabetes insipidus, osteoporosis.
• Toxicity
  
  • Hypokalemic metabolic alkalosis, hyponatremia, hyperGlycemia, hyperLipidemia, hyperUricemia, and hyperCalcemia.
    
    • HyperGLUC**
  • Sulfa allergy.

Question 7

K+-sparing diuretics

• Examples
• Mechanism
• Clinical use
• Toxicity

Answer 7

• Examples
  
  • Spironolactone and eplerenone; Triamterene, and Amiloride.
  • The K+ STAys.
• Mechanism
  
  • Spironolactone and eplerenone are competitive aldosterone receptor antagonists in the cortical collecting tubule.
  • Triamterene and amiloride act at the same part of the tubule by blocking Na+ channels in the CCT.
• Clinical use
  
  • Hyperaldosteronism, K+ depletion, CHF.
• Toxicity
  
  • Hyperkalemia (can lead to arrhythmias), endocrine effects with spironolactone (e.g., gynecomastia, antiandrogen effects).

Question 8

Diuretics: electrolyte changes

• Urine NaCl
• Urine K+
• Urine Ca2+

Answer 8

• Urine NaCl 
  
  • Increase (all diuretics except acetazolamide).
  • Serum NaCl may decrease as a result.
• Urine K+ 
  
  • Increase with loop and thiazide diuretics.
  • Serum K+ may decrease as a result.
• Urine Ca2+ 
  
  • Increase with loop diuretics: decrease paracellular Ca2+ reabsorption Ž–> hypocalcemia.
  • Decrease with thiazides: Enhanced paracellular Ca2+ reabsorption in distal tubule.

Question 9

Diuretics: electrolyte changes:
Blood pH

• Decrease
• Increase

Answer 9

• Decrease (acidemia)
  
  • Carbonic anhydrase inhibitors decrease HCO3- reabsorption.
  • K+ sparing aldosterone blockade prevents K+ secretion and H+ secretion.
  • Additionally, hyperkalemia leads to K+ entering all cells (via H+/K+ exchanger) in exchange for H+ exiting cells.
• Increase (alkalemia)
  
  • Loop diuretics and thiazides cause alkalemia through several mechanisms:
  • Volume contraction –> increased AT II –>Ž increased Na+/H+ exchange in proximal tubule –>Ž increasedŽ HCO3- reabsorption (“contraction alkalosis”)
  • K+ loss leads to K+ exiting all cells (via H+/K+ exchanger) in exchange for H+ entering cells
  • In low K+ state, H+ (rather than K+) is exchanged for Na+ in cortical collecting tubule, –>Ž alkalosis and “paradoxical aciduria”

Question 10

ACE inhibitors

• Examples
• Mechanism
• Clinical use
• Toxicity

Answer 10

• Examples
  
  • Captopril, enalapril, lisinopril
• Mechanism
  
  • Inhibit ACE –>Ž decrease angiotensin II –>Ž decrease GFR by preventing constriction of efferent arterioles.
  • Levels of renin increase as a result of loss of feedback inhibition.
  • Inhibition of ACE also prevents inactivation of bradykinin, a potent vasodilator.
  • Angiotensin II receptor blockers (-sartans) have effects similar to ACE inhibitors but do not increase bradykinin –>Ž decreased risk of cough or angioedema.
• Clinical use
  
  • Hypertension, CHF, proteinuria, diabetic nephropathy.
  • Prevent unfavorable heart remodeling as a result of chronic hypertension.
• Toxicity
  
  • Cough, Angioedema (contraindicated in C1 esterase inhibitor deficiency), Teratogen (fetal renal malformations), increased Creatinine (decreased GFR), Hyperkalemia, and Hypotension.
    
    • Captopril’s CATCHH
  • Avoid in bilateral renal artery stenosis, because ACE inhibitors will further decrease GFR –>Ž renal failure.